Features of early and late recurrence versus de novo metastatic ccRCC: Findings from JAVELIN Renal 101.

544 Background: Many patients with clear cell renal cell carcinoma (ccRCC) recur after nephrectomy, yet how these recurrences differ clinically and biologically from de novo metastatic (DNM) disease is not well understood. In this post-hoc analysis, we sought to characterize DNM versus early, intermediate, and late recurrent (ER, IR, and LR) ccRCC. Methods: JAVELIN Renal 101 was a Ph 3 trial comparing avelumab + axitinib (Av+Ax) to sunitinib (Su). Patients were categorized as DNM if presenting with metastatic disease (n=267) or recurrent after nephrectomy: ER (<12 months, n=137), IR (1-5 years, n=144), and LR (>5 years, n=139). Groups were compared across key clinical and RNA features. The prognostic impact of recurrence type was assessed using Cox models – adjusting for age, IMDC, and treatment arm. To assess whether treatment efficacy differed by recurrence type, subgroup analyses were performed on Av+Ax versus Su, with an interaction term to test for effect modification. Results: DNM and ER shared aggressive features (≥T3 in 63% and 66%; grade 4 in 42% and 43%), in contrast to features of LR (29% ≥T3+ and 13% grade 4). Biologically, LR also differed, including higher angiogenic scores (Table 1). In adjusted analyses, all recurrence groups had improved survival compared to de novo metastatic disease; (LR: PFS & OS HR 0.64 & 0.49, p < 0.001). Median OS for DNM, ER, IR, and LR was 24, 44, 58, and 61 months, respectively. In subgroup analyses, Av + Ax versus Su was associated with better PFS in ER and DNM (HR= 0.49 & 0.67, p<0.01) in contrast to IR and LR (HR= 0.84 & 0.84, p>0.3) with interaction suggesting differing treatment effect (p=0.015). Conclusions: ER and LR ccRCC are biologically and clinically distinct, with ER resembling DNM ccRCC while LR exhibit more indolent features and angiogenic profiles. Recurrence is associated with better survival than DNM. ER and DNM disease may uniquely benefit from the addition of immune checkpoint inhibition. Select Features De Novo Metastatic (DNM) N = 267 Early Recurrence (ER: <12 months) N = 137 Intermediate Recurrence(IR: 1-5 years) N = 144 Late Recurrence (LR: >5 year) N = 139 p-value Initial ≥T3 168 (63%) 90 (66%) 76 (53%) 41 (29%) <0.0001 Grade 4 89 (42%) 56 (43%) 38 (27%) 16 (13%) <0.0001 Sarcomatoid 37 (14%) 20 (15%) 16 (11%) 3 (2.2%) 0.0015 PD-L1+ 169 (70%) 101 (76%) 83 (63%) 77 (63%) 0.058 No IMDC Risk Factors* 85 (32%) 63 (46%) 79 (55%) 82 (59%) <0.0001 RNA Data(n=583) Angio Signature -0.09(-0.19, 0.02) -0.10-0.23, 0.03 0.08-0.05, 0.22 0.220.07, 0.37) 0.0006 15-Gene Prognostic Score 0.1(-0.62, 0.90) 0.7(-0.15,1.6) 0.2(-0.68,1.0) -1.9(-3.0,-0.86) 0.0036 *Excluding time to diagnosis <12 months.